Essay
The Latest Mania: Selling Bipolar Disorder
David Healy
O
ne of the most famous direct-
to-consumer television adverts
for a drug begins with a
vibrant woman dancing late into the
night. A background voice says, “Your
doctor probably never sees you when
you feel like this.” The advert cuts to
a shrunken and glum figure, and the
voiceover now says, “This is who your
doctor usually sees.” Cutting again to
the woman, in active shopping mode,
clutching bags with the latest brand
names, we hear: “That’s why so many
people with bipolar disorder are being
treated for depression and not getting
any better—because depression is only
half the story.” We see the woman again
depressed, looking at bills that have
arrived in the post before switching to
seeing her again energetically painting
her apartment. “That fast- talking,
energetic, quick tempered, overdoing
it, up-all-night you,” says the voiceover,
“probably never shows up at the
doctor’s office, right?”
No drugs are mentioned. But
viewers are encouraged to log onto
www.bipolarawareness.com, which
takes them to a Web site called
“Bipolar Help Center,” sponsored
by Lilly Pharmaceuticals, the makers
of olanzapine (Zyprexa). The Web
site contains a “mood disorder
questionnaire” (http:⁄⁄www.
bipolarhelpcenter.com/resources/
mdq.jsp). In the television advert, we
see our heroine logging onto www.
bipolarawareness.com and finding this
questionnaire. The voice encourages
the viewer to follow her example: “Take
the test you can take to your doctor, it
can change your life….getting a correct
diagnosis is the first step in treating
The Essay section contains opinion pieces on topics
of broad interest to a general medical audience.
PLoS Medicine | www.plosmedicine.org
DOI: 10.1371/journal.pmed.0030185.g001
Figure 1. Articles Elicited by Medline Using the Mesh Term “Mood Stabilizer”
bipolar disorder. Help your doctor to
help you.”
This advert markets bipolar disorder.
The advert can be read as a genuine
attempt to alert people who may
be suffering from one of the most
debilitating and serious psychiatric
diseases—manic-depressive illness.
Alternatively, the advert can be read as
an example of what has been termed
disease mongering [1]. Whichever it
is, it will reach beyond those suffering
from a mood disorder to others who will
as a consequence be more likely to see
aspects of their personal experiences
in a new way that will lead to medical
consultations and in a way that will shape
the outcome of those consultations.
Adverts that encourage “mood
watching” risk transforming variations
from an emotional even keel into
potential indicators of latent or actual
bipolar disorder. This advert appeared
in 2002 shortly after Lilly’s antipsychotic
olanzapine had received a license for
treating mania. The company was also
running trials aimed at establishing
olanzapine as a “mood stabilizer,” one of
which was recently published [2].
Mood Stabilization
From the 1950s on, the depressions
of manic-depressive illness have been
0441
treated with antidepressants and the
manias with antipsychotics or lithium.
Lithium was the only agent thought
to be prophylactic against further
episodes of manic-depressive illness
[3]. But lithium was not originally
referred to as a mood stabilizer. The
term “mood stabilizer” had barely
been heard of before 1995 when
Abbott Laboratories got a license
Funding: The author received no specific funding to
write this article.
Competing Interests: DH has been a speaker,
consultant, or clinical trialist for Lilly, Janssen,
SmithKline Beecham, Pfizer, Astra-Zeneca, Lorex-
Synthelabo, Lundbeck, Organon, Pierre-Fabre, Roche,
and Sanofi. He has also been an expert witness in
ten legal cases involving antidepressants and suicide
or homicide and one case involving the patent on
olanzapine (Zyprexa). None of these interests played
any part in the submission or preparation of this
paper.
Citation: Healy D (2006) The latest mania: Selling
bipolar disorder. PLoS Med 3(4): e185.
DOI: 10.1371/journal.pmed.0030185
Copyright: © 2006 David Healy. This is an
open-access article distributed under the terms
of the Creative Commons Attribution License,
which permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
David Healy is at the North Wales Department of
Psychological Medicine, Cardiff University, Cardiff,
Wales, United Kingdom. E-mail: healy_hergest@
compuserve.com
April 2006 | Volume 3 | Issue 4 | e185
for using the anticonvulsant sodium
valproate (Depakote) for treating
acute mania [4].
After 1995, there was a dramatic
growth in the frequency with which
the term “mood stabilizer” appeared
in the title of scientific articles (see
Figure 1). By 2001, more than a
hundred article titles a year featured
this term. Repeated reviews make it
clear that the academic psychiatric
community still has not come to a
consensus on what the term “mood
stabilizer” means [5–7]. But this lack
of consensus did not get in the way of
the message that patients with bipolar
disorders needed to be detected
and once detected needed mood
stabilizers, and perhaps should only be
given these drugs and not any other
psychotropic drugs [8,9].
The growth of awareness
of mood stabilization
was sensational.
The first group of drugs to colonize
this new mood stabilizer niche was
anticonvulsants. Anticonvulsants are
beneficial in epilepsy and were until
recently widely thought to be beneficial
by quenching the increased risk of
succeeding epileptic fits brought
about by fits that have gone before.
Robert Post in the 1980s suggested
that anticonvulsants might stabilize
moods by a comparable quenching
of the kindling effect of an episode of
mood disorders on the risk of further
episodes [10]. It was this idea that
provided a pharmacological rationale
for treatment of bipolar disorders that
was so attractive to pharmaceutical
companies, and, in their hands,
the growth of awareness of mood
stabilization and of bipolar disorders
was sensational.
Bipolar disorders entered the DSM
(Diagnostic and Statistical Manual of
Mental Disorders) in 1980. At the time,
the criteria for bipolar I disorder
(classic manic-depressive illness)
involved an episode of hospitalization
for mania. Since then, the community-
based disorders bipolar II disorder,
bipolar disorders NOS (not otherwise
specified), and cyclothymia have
emerged. With their emergence,
estimates for the prevalence of bipolar
disorders have risen from 0.1% of
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the population having bipolar I
disorder (involving an episode of
hospitalization for mania) [11] to 5%
or more when the definition of bipolar
disorders includes the aforementioned
community disorders [12]. A range of
academic institutions has also grown
more interested in the condition.
There has always been a rationale
to using antipsychotics in bipolar
disorders, as they are effective in
acute manic states [13,14]. However,
no companies making antipsychotics
had previously sought a license
for prophylaxis against bipolar
disorders. Against a background of
epidemiological studies indicating that
the prevalence of bipolar disorders
might be greater than previously
thought [15,16], and growing academic
interest in the condition, Lilly, Janssen,
and Astra-Zeneca, the makers of the
antipsychotics olanzapine, risperidone,
and quetiapine (Seroquel),
respectively, marched in on the new
territory to market these drugs for
prophylaxis of bipolar disorder. This, in
turn, greatly expanded the number of
companies with an interest in making
the “bipolar market.” There was,
however, no consensus on a theoretical
rationale that would lead the average
clinician to think these three drugs
might “quench” the propensity to
further affective episodes, as opposed
to simply assist in the management of
acute manic states.
But the increased prevalence
estimates were based on community
surveys that had no clear disability
criterion, while acute treatment
trials of antipsychotics for mania,
and prophylactic trials of lithium for
manic-depressive illness, have for the
most part been conducted on bipolar
I disorder. This necessarily raises the
prospect that increased efforts to detect
and to treat people risks crossing the
line where the benefits of treatment
outweigh its risks.
Along with this expansion in
prevalence estimates came new
journals, Bipolar Disorders (http:⁄⁄www.
blackwellpublishing.com/journal.
asp?ref=1398-5647) and the Journal
of Bipolar Disorders (published by
Lippincott, Williams, and Wilkins), a
slew of bipolar societies, and annual
conferences, many heavily funded by
pharmaceutical companies. There
is a growing amount of patient Web
site and patient support materials
0442
that in the case of Zyprexa state that
“bipolar disorder is often a lifelong
illness needing lifelong treatment;
symptoms come and go, but the illness
stays; people feel better because the
medication is working; almost everyone
who stops taking the medication will
get ill again and the more episodes
you have, the more difficult they are to
treat” [17]. Information available from
Janssen (the makers of Risperdal) states
“medicines are crucially important in
the treatment of bipolar disorders.
Studies over the past twenty years
have shown beyond the shadow of
doubt that people who receive the
appropriate drugs are better off in the
long term than those who receive no
medicine” [18].
What Lies Beneath
There is, however, much less evidence
than many might think to support
these claims for the prophylactic drug
treatment of manic-depressive illness
(bipolar I). And there is almost no
evidence to support such claims in the
case of whatever community disorders
(bipolar II, bipolar NOS, cyclothymia)
are now being pulled into the manic-
depressive net by the lure of bipolar
disorder.
With the possible exception of
lithium for bipolar I disorder, there
are no randomized controlled trials
to show that patients with bipolar
disorders in general who receive
psychotropic drugs are better in the
long term than those who receive no
medicine [19]. This may stem in part
from difficulties in conducting trials
on psychotropic drugs that last more
than a few weeks in conditions as
complex as manic-depressive illness.
One short-term, randomized, placebo-
controlled trial (in which patients were
only followed for up to 48 weeks) that
some see as a basis for claiming that
olanzapine may be prophylactic in
bipolar disorder [2] has been regarded
by others as indicating that this drug
produces a withdrawal-induced
decompensation when stopped [20].
Even in the case of lithium, there
is some dispute over what has been
demonstrated [19], with the best
evidence stemming from large open
studies in dedicated lithium services
rather than from randomized trials
[21].
This evidence of benefit for
one agent (lithium) and possible
April 2006 | Volume 3 | Issue 4 | e185

DOI: 10.1371/journal.pmed.0030185.g002
Figure 2. Author’s Graph of p-Value
Function Based on Data in [30]
(Illustration: Sapna Khandwala)
benefit for one more (olanzapine)
must be weighed against two harms
associated with use of antipsychotics:
(1) a consistent body of evidence
indicates that regular treatment with
antipsychotics in the longer run
increases mortality [22–26]; and (2)
there is evidence that in placebo-
controlled trials of antipsychotics
submitted in application for
schizophrenia licenses there is a
statistically significant excess of
completed suicides on active treatment
[27]. A range of problems associated
with antipsychotics, from increased
mortality to tardive dyskinesia, never
show up in the short-term trials aimed
at demonstrating treatment effects in
psychiatry.
But aside from these hazards, there
are also grounds to question whether
the treatment effects that some think
have been demonstrated in bipolar
disorder trials translate into therapeutic
efficacy. If use of these agents based
on demonstrated effects leads on
to efficacy, admissions for bipolar
disorder might be expected to fall,
but the evidence for this is difficult
to find. In North Wales before the
advent of modern pharmacotherapy,
patients with bipolar I disorder had
on average four admissions every ten
years. In contrast, against a background
of a constant incidence of bipolar I
disorder, and dramatic improvements
in service provision, bipolar I patients
show a 4-fold increase in the prevalence
of admissions despite being treated
with the very latest psychotropic
medications [11]. This is not ordinarily
what happens when treatments “work,”
but quite often is what happens when
treatments have effects.
The selling of bipolar disorder
stresses that the disorder takes
a fearsome toll of suicides. And
indeed the controversy surrounding
the provocation of suicide by
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antidepressants has been recast by
some as a consequence of mistaken
diagnosis. If the treating physician
had only realized the patient was
bipolar, they would not have mistakenly
prescribed an antidepressant. Because
of the suicide risk traditionally linked
to patients with bipolar disorders
who needed hospitalisation, most
psychiatrists would find it difficult
to leave any person with a case of
bipolar disorder unmedicated. Yet,
the best available evidence shows that
unmedicated patients with bipolar
disorder do not have a higher risk of
suicide.
Storosum and colleagues analyzed
all placebo-controlled, double-blind,
randomized trials of mood stabilizers
for the prevention of manic/depressive
episode that were part of a registration
dossier submitted to the regulatory
authority of the Netherlands, the
Medicines Evaluation Board, between
1997 and 2003 [28]. They found four
such prophylaxis trials. They compared
suicide risk in patients on placebo
compared with patients on active
medication. Two suicides (493/100,000
person- years of exposure) and eight
suicide attempts (1,969/100,000
person-years of exposure) occurred
in the group given an active drug
(943 patients), but no suicides and
two suicide attempts (1,467/100,000
person-years of exposure) occurred
in the placebo group (418 patients).
Based on these absolute numbers from
these four trials, I have calculated (see
Figure S1 showing calculation, and
see Figure 2) that active agents are
most likely to be associated with a 2.22
times greater risk of suicidal acts than
placebo (95% CI 0.5, 10.00).
The Bipolar Future
Until recently the general clinical
wisdom was that it was very rare for
manic-depressive illness to have an
onset in the preteen years. But there
is now a surge of diagnoses of bipolar
disorder in American children [29,30],
even though these children do not
meet the traditional criteria for bipolar
I disorder (from the Diagnostic and
Statistical Manual of Mental Disorders)
[31]. The mania for pediatric bipolar
disorder hit the front cover of the
American edition of Time in August
2002, which featured nine-year-old
Ian Palmer and a cover title Young and
Bipolar, with a strapline, why are so many
0443
kids being diagnosed with the disorder, once
known as manic-depression?
A recent book, The Bipolar Child
[32], brings out the extent of the
current mania. Published in 2000,
this book sold 70,000 hardback
copies in six months in the US. As the
Star Telegram reported in July 2000
[33], The Bipolar Child made all the
difference to Heather Norris, whose
mother, after reading it, challenged
her physician to correct Heather’s
diagnosis from ADHD, treatment of
which had made her daughter worse,
to the correct diagnosis of bipolar
disorder. As a result, Heather, at the
age of two, became the youngest child
in Tarrant County, Texas, to have a
diagnosis of bipolar disorder. The Star
Telegram article noted that “along with
the insurance woes, lack of treatment
options and weak support systems that
plague most families with mentally ill
children, parents of the very young
face additional challenges. Finding
the proper diagnosis for treatment is
a nightmare because of scant research
into childhood mental illness and the
drugs that combat them.”
If we consider adults alone for a
moment, there is already the potential
for creating an “epidemic” of bipolar
disorder, because people are being
diagnosed with the condition based on
operational criteria that depend upon
subjective judgements (rather than an
objective criterion of disability, such as
hospitalization or being off work for a
month). The potential is compounded
in the pediatric domain by the fact
that the diagnosis is based on caregiver
reports with little scope in most clinical
practice for critical scrutiny of the
social forces that may lead to these
reports. Experts that appear willing
to go so far as to accept the possibility
that the first signs of bipolar disorder
may be patterns of overactivity in
utero [32] can only further compound
these problems. If the resulting
diagnoses were provisional, aimed
at researching the natural history of
childhood irritability, rather than
reaching diagnoses that lead on to
pharmacotherapy, there might be
little problem. However, drugs such as
Zyprexa and Risperdal are now being
used for preschoolers in America with
little questioning of this development
[31].
Far from research bringing a
skeptical note to bear on clinical
April 2006 | Volume 3 | Issue 4 | e185
enthusiasm, it appears to be adding
fuel to the fire. What might once have
been thought of as sober institutions,
such as Massachusetts General
Hospital, have run trials of Risperdal
and Zyprexa on children with a
mean age of four years old [34,35].
Massachusetts General Hospital in fact
recruited trial participants by running
its own television adverts featuring
clinicians and parents alerting parents
to the fact that difficult and aggressive
behavior in children aged four and
up might stem from bipolar disorder.
This does more than recruit patients
with a clear disorder; it suggests that
everyday behavioral difficulties may
be better seen in terms of a disorder.
Given that bipolar disorder in children
is all but unrecognised outside the
US, it seems likely that a significant
proportion of these children will not
meet conventional DSM criteria for
bipolar I disorder. And given that it is
all but impossible for a short-term trial
of sedative agents in pediatric states
characterized by overactivity not to show
some rating scale changes that can be
regarded as beneficial, the outcomes
of this research are likely to appear to
validate the diagnosis and increase the
pressure for treatment.
Several years after Heather Norris
was diagnosed with bipolar disorder,
the rationale for mood stabilization
was greatly weakened by the results
of the largest-ever randomized
trial of immediate versus deferred
anticonvulsant therapy for people
who had experienced a single seizure
[36]. The trial found that although
immediate antiepileptic drug
treatment reduces the occurrence
of seizures in the next 1–2 years,
such treatment does not affect long-
term remission in individuals with
single or infrequent seizures. The
use of psychotropic medication for
bipolar disorders was based on an
analogy with epilepsy, rather than
on demonstrations of proven clinical
benefits over the long term or on
the basis of a correction of a known
pathophysiology. The absence of a
solid theoretical or empirical basis
for using psychotropic medication as
“mood stabilizers” raises questions as
to what lies in store for the Heather
Norris’s and others of this world
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exposed to these complex psychotropic
agents from such a young age. !
Supporting Information
Figure S1. Episheet Showing Author’s
Relative Risk Calculation, Based on Data in
[30]
Found at DOI: 10.1371/journal.
pmed.0030185.sg001 (792 KB XLS).
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